PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels.

Aberrations in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway constitute a subclass of congenital disorders of glycosylation, and mutations in seven genes involved in this pathway have been identified. Among them, mutations in PIGV and PIGO, which are involved in the late stages of GPI-anchor synthesis, and PGAP2, which is involved in fatty-acid GPI-anchor remodeling, are all causative for hyperphosphatasia with mental retardation syndrome (HPMRS). Using whole exome sequencing, we identified novel compound heterozygous PIGO mutations (c.389C>A [p.Thr130Asn] and c.1288C>T [p.Gln430*]) in two siblings, one of them having epileptic encephalopathy. GPI-anchored proteins (CD16 and CD24) on blood granulocytes were slightly decreased compared with a control and his mother. Our patients lacked the characteristic features of HPMRS, such as facial dysmorphology (showing only a tented mouth) and hypoplasia of distal phalanges, and had only a mild elevation of serum alkaline phosphatase (ALP). Our findings therefore expand the clinical spectrum of GPI-anchor deficiencies involving PIGO mutations to include epileptic encephalopathy with mild elevation of ALP.

The phosphate binder equivalent dose.

Phosphate binders include calcium acetate or carbonate, sevelamer hydrochloride or carbonate, magnesium and lanthanum carbonate, and aluminum carbonate or hydroxide. Their relative phosphate-binding capacity has been assessed in human, in vivo studies that have measured phosphate recovery from stool and/or changes in urinary phosphate excretion or that have compared pairs of different binders where dose of binder in each group was titrated to a target level of serum phosphate. The relative phosphate-binding coefficient (RPBC) based on weight of each binder can be estimated relative to calcium carbonate, the latter being set to 1.0. A systematic review of these studies gave the following estimated RPBC: for elemental lanthanum, 2.0, for sevelamer hydrochloride or carbonate 0.75, for calcium acetate 1.0, for anhydrous magnesium carbonate 1.7, and for "heavy" or hydrated, magnesium carbonate 1.3. Estimated RPBC for aluminum-containing binders were 1.5 for aluminum hydroxide and 1.9 for aluminum carbonate. The phosphate-binding equivalent dose was then defined as the dose of each binder in g × its RPBC, which would be the binding ability of an equivalent weight of calcium carbonate. The phosphate-binding equivalent dose may be useful in comparing changes in phosphate binder prescription over time when multiple binders are being prescribed, when estimating an initial binder prescription, and also in phosphate kinetic modeling.

Transient benign hyperphosphatasemia due to COVID-19: the first case report.

OBJECTIVES: Coronavirus disease (COVID-19) rapidly spread worldwide in a few months and was declared as a worldwide pandemic by WHO in March 2020. Transient benign hyperphosphatasemia (THI) is a benign condition associated with marked elevation of alkaline phosphatase (ALP) without any other kidney, bone, and liver pathologies. CASE PRESENTATION: Herein, we report a previously healthy 16-month-old female patient who developed a secondary transient benign hyperphosphatasemia associated with SARS-CoV-2. Patient whole family's SARS-CoV-2 real-time reverse transcription-polymerase chain reaction (RT-PCR) results were positive. Since THI is a diagnosis of exclusion, other reasons that may cause ALP elevation should be ruled out. ALP activity decreased and turned to normal ranges within the following month. THI has been reported to be in association with various conditions. Its relationship with many viruses has been reported previously. CONCLUSIONS: If ALP elevation is detected in patients with COVID 19 due to the increasing number of infections, THI should be considered if there is no other accompanying pathology.

Benefits of sevelamer on markers of bone turnover in Taiwanese hemodialysis patients.

BACKGROUND/PURPOSE: Sevelamer hydrochloride is a recently developed phosphate binder, which is a quaternary amine anion exchanger without calcium or aluminum. Sevelamer is effective in controlling hyperphosphatemia without increasing the calcium load in chronic hemodialysis (HD) patients. We investigated whether sevelamer restored bone metabolism in chronic HD patients. METHODS: An 8-week, prospective, open-label, randomized study was conducted after a 2-week washout period in chronic hyperphosphatemic HD patients. This study compared the effect of sevelamer on markers of bone turnover with that of calcium acetate, as stratified by baseline serum intact parathyroid hormone (iPTH) level. RESULTS: There was no difference in the changes of serum phosphorus, calcium-phosphorus product and serum iPTH between the sevelamer and the calcium acetate groups. However, more hypercalcemic events (12%) were documented under calcium acetate treatment. In patients with hypoparathyroidism, calcium acetate treatment decreased serum iPTH at the end of the study, while sevelamer did not. Increased serum alkaline phosphatase levels were found among patients receiving sevelamer treatment compared with those who received calcium acetate treatment. In those patients receiving sevelamer, the serum alkaline phosphatase level was also positively correlated to the sevelamer dosage (r = 0.246, p = 0.013). CONCLUSION: Sevelamer effectively reduces serum phosphorus with a lower incidence of hypercalcemic effects in HD patients. Sevelamer is an effective means of treatment for chronic hyperphosphatemic HD patients, especially those with hypoparathyroidism.

Hyperphosphatasia with mental retardation syndrome type 4 In two siblings-expanding the phenotypic and mutational spectrum.

Hyperphosphatasia with mental retardation syndrome (HPMRS) (OMIM # 239300), is an autosomal recessive disease with phenotypic variability, ranging from mild nonsyndromic intellectual disability to syndromic form with severe intellectual disability, seizures, elevated alkaline phosphatase, brachytelephalangy and facial dysmorphism, Six subgroups of HPMRS were defined in which pathogenic mutations affect genes involved in either synthesis or remodeling of the anchor proteins. Among these, PGAP3 mutations are associated with HPMRS type 4. We report two siblings with a novel homozygous variant in PGAP3 expanding both the phenotypic findings and the mutational spectrum of HPMRS type 4. Developmental delay, hypotonia, facial dysmorphism were the consistent findings with HPMRS in our patients. Large anterior fontanel size, gum hypertrophy, pes equinovarus, concentric ventricle hypertrophy, frontoparietal atrophy and dysphagia were the findings of our patients that have been reported for the first time in this syndrome. Although there is an extensive list of differential diagnoses in patients with developmental delay and hypotonia, the recognizable pattern of facial features, parental consanguinity and mild to moderate serum ALP elevation should be sufficiently suggestive of HPMRS type 4.

The association between periodontal conditions, inflammation, nutritional status and calcium-phosphate metabolism disorders in hemodialysis patients.

OBJECTIVES: To analyze the association between periodontal conditions and inflammation, nutritional status and calcium-phosphate metabolism disorders in hemodialysis (HD) patients. MATERIAL AND METHODS: We analyzed 128 HD patients divided into two groups: dentate (n = 103) and edentulous (n=25). The following items were assessed: baseline characteristics, age at the start and duration of HD, biochemical data: C-reactive protein (CRP), serum albumin, calcium, phosphorus, alkaline phosphatase, parathormone. A single dentist performed a complete dental/periodontal examination, including parameters of oral hygiene and gingival bleeding. RESULTS: One person had healthy periodontium, 62.14% of the patients had gingivitis, and 36.9% had moderate or severe periodontitis. The age at HD onset had a positive impact on periodontal status and negatively correlated with the number of teeth. A positive correlation between age and CRP level and negative correlations between age and serum albumin and phosphorus were found. Pocket depth (PD) was negatively correlated with serum albumin. The number of teeth was negatively correlated with serum CRP. CONCLUSIONS: High prevalence and severity of periodontal disease are observed in hemodialysis patients. There is a high probability that periodontal disease may be present at the early stages of chronic kidney disease (CKD) before the hemodialysis onset.

Optimising the treatment of hyperphosphatemia and vascular calcification in chronic kidney disease.

Accelerated atherosclerosis and vascular calcifications (VC) play a central role in the pathogenesis of cardiovascular disease in chronic kidney disease (CKD) patients. Mineral metabolism disorders and increased serum calcium-phosphate product have been recently investigated as inducing factors of cardiovascular calcification. In fact, cardiovascular disease in renal failure appears greatly associated with bone metabolism alterations. Recently, the treatment of hyperphosphatemia in CKD patients changed from either calcium- or aluminium-based phosphate-binders to new free-calcium and aluminium phosphate binders, such as sevelamer hydrochloride and lanthanum carbonate. Therefore, control of serum phosphate in CKD patients becomes crucial in preventing increases in calcium-phosphate product, secondary hyperparathyroidism and ultimately VC.

Emerging drugs for hyperphosphatemia.

Cardiovascular mortality is the leading cause of death in the uremic patient. Hyperphosphatemia is considered an independent risk factor associated with cardiovascular morbidity and mortality in dialysis patients. As phosphate control is not efficient with diet or dialysis, phosphate binders are commonly prescribed in patients with chronic renal failure. Aluminum salts, the first phosphate binders, even if effective, have several side effects due to their deposition in CNS, bone and hematopoietic cells. Calcium-containing phosphate binders, used in the last 15 years, increase total body calcium load and may exacerbate metastatic calcification, thus, increasing the risk of cardiovascular mortality. Recently two new compounds non-aluminum and non-calcium phosphate binders, sevelamer hydrochloride and lanthanum carbonate, have been introduced. Sevelamer, besides the effect on phosphate, has been associated with reduction of coronary and aortic calcification and with other pleiotropic effects especially on lipid metabolism. Lanthanum carbonate has similar phosphate control to calcium-based binders with less incidence of hypercalcemia but long-term clinical studies are needed for testing long-term exposure. Recently the authors found in dialysis patients, that salivary phosphorus correlated with serum phosphorus. Therefore, they supposed that the use of salivary phosphate binders could reduce its absorption and represent a chance for reducing the serum phosphate concentration in uremic patients.

Lanthanum: new drug. Hyperphosphataemia in dialysis patients: more potential problems than benefits.

(1) In dialysis patients with chronic renal failure, hyperphosphataemia can cause osteorenal dystrophy, leading to bone pain, fractures and excess cardiovascular mortality. In addition to a low-phosphorus diet and dialysis, phosphorus chelators are usually needed to control blood phosphorus levels. The first choice is calcium carbonate, and sevelamer is an alternative. (2) Lanthanum carbonate, a phosphorus chelator, is now also licensed for the treatment of hyperphosphataemia in dialysis patients with chronic renal failure. (3) In addition to three dose-finding placebo-controlled studies, clinical evaluation includes 2 comparative randomised unblinded trials: one 6-month trial versus calcium carbonate and a 2-year trial versus other phosphorus chelators. During these trials, lanthanum was no more effective than the comparators in terms of effects on the mortality rate, incidence of fractures, or blood phosphorus level. (4) During these trials, adverse events attributed to treatment were more frequent with lanthanum than with the other phosphorus chelators. The main problems were gastrointestinal disorders (nausea, vomiting, diarrhoea, constipation and abdominal pain), headaches, seizures, and encephalopathy. (5) The accumulation of lanthanum in the bones and brain is troubling. The known long-term adverse effects of aluminium, another trivalent cation with weak gastrointestinal absorption, suggest that caution is also required with lanthanum. (6) In practice, when a phosphorus chelator is needed to treat hyperphosphataemia in dialysis patients with chronic renal failure, calcium carbonate is the first choice and sevelamer remains the best alternative.

A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers.

Mutations in genes involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor cause autosomal recessive glycosylation defects, with a wide phenotypic spectrum of intellectual disability, seizures, minor facial dysmorphism, hypotonia, and elevated serum alkaline phosphatase. We now describe consanguineous Bedouin kindred presenting with an autosomal recessive syndrome of intellectual disability and elevated serum alkaline phosphatase. Genome-wide linkage analysis identified 6 possible disease-associated loci. Whole-exome sequencing followed by Sanger sequencing validation identified a single variant in PGAP2 as the disease-causing mutation (C.554G>A; p.185(R>Q)), segregating as expected within the kindred and not found in 150 Bedouin controls. The mutation replaces a highly conserved arginine residue with glutamine within the Frag1 (FGF receptor activating) domain of PGAP2. Interestingly, this mutation is a known dbSNP variant (rs745521288, build 147) with a very low allele frequency (0.00000824 in dbSNP, no homozygotes reported), highlighting the fact that dbSNP variants should not be automatically ruled out as disease-causing mutations. We further showed that PGAP2 is ubiquitously expressed, but in line with the disease phenotype, it is highly transcribed in human brain, skeletal muscle, and liver. Interestingly, a mild phenotype of slightly elevated serum levels of alkaline phosphatase and significant learning disabilities was observed in heterozygous carriers.

A new era in phosphate binder therapy: what are the options?

Dietary restriction of phosphorus and current dialysis prescription are unable to maintain phosphorus levels within the recommended range (2.7-5.5 mg/dl) in patients with advanced chronic kidney disease (CKD). Therefore, phosphate binders that limit the absorption of dietary phosphorus are commonly prescribed for this patient group. The first phosphate binders were introduced more than 30 years ago and included aluminum salts; however, although effective binders, the use of these agents was subsequently restricted because of concerns over aluminum accumulation in the central nervous system, bone, and hematopoietic cells. In subsequent years, calcium salts, namely calcium carbonate and calcium acetate, became the most widely used phosphate binders; however, increasing evidence now suggests that prolonged use of these agents increases the total body calcium load, induces adynamic bone, and potentially increases the risk of cardiovascular and soft tissue calcification. Sevelamer is the first phosphate-binding agent that is non-absorbed, calcium-free, and metal-free. To date, this agent has been shown to effectively control serum phosphorus levels in patients with CKD. It may also attenuate coronary and aortic calcification and has a number of other beneficial effects on lipid metabolism and inflammation among others. Lanthanum carbonate is another new agent that is reported to provide similar phosphate control to calcium-based phosphate binders but concerns that the long-term administration of such compound may lead to tissue accumulation may limit its use.

Pleiotropic effects of the non-calcium phosphate binder sevelamer.

The number of chronic kidney disease (CKD) patients and related adverse outcomes has dramatically increased worldwide in the past decade. Therefore, numerous experimental and clinical studies have recently addressed the underlying mechanisms, in particular the marked increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients with advanced stage of CKD. Its control by calcium-containing phosphate binders is effective, but at the price of potentially noxious calcium overload. Sevelamer hydrochloride is a phosphate binder that offers an effective control of hyperphosphatemia as calcium-rich binders but without increase of calcium load. Beyond the control of phosphate, sevelamer seems to exert pleiotropic effects which include the correction of lipid abnormalities and the clearance of some uremic toxins.

Blast from the past: the aluminum's ghost on the lanthanum salts.

Hyperphosphatemia is a common serious complication of chronic renal diseases, which needs appropriate continuous treatment in order to avoid ominous side effects. Therefore, oral chelating agents able to avoid phosphate absorption by the gut are mandatory. In the past, Aluminium salts, and more recently Calcium and Magnesium salts, and a synthetic resin polyallylamine hydrochloride have been employed, but Aluminium was later abandoned, because it has been a silent killer of many uremic patients, due to subtle absorption eventually leading to toxicity on Central Nervous System and bone, with allucinations, seizures, dementia, and osteomalacia, bone pain, fracturing osteodystrophy, and death. Recently, a new chelating agent able to bind dietary phosphate, namely Lanthanum carbonate has been introduced, with a proven efficacy profile for short-term treatment. However, after careful examination of the very few scientific papers available to date, we strongly advise caution before adopting, at present, lanthanum carbonate as a phosphate binder in uremic patients. In fact, notwithstanding minimized, some data are worrying: first, Lanthanum ions are absorbed, though at a minimal extent, by human gut; 2) pharmacokinetic evaluations show a greater exposure to Lanthanum in uremic patients;3) Lanthanum concentration is increased tenfold in blood and fivefold in bone after short-term supplementation in uremic patients; 4) there is no proofs that Lanthanum cannot cross the blood brain barrier in uremic patients; 5)Lanthanum has many biological effects and is potentially highly toxic. The Aluminum story should serve as cautionary tale when considering the use of new metal ions.

Treatment of alcoholic acidosis: the role of dextrose and phosphorus.

We have made serial metabolic observations in 18 acute episodes of alcoholic ketoacidosis in ten patients. Data from patients treated with only saline initially were compared to data from patients who received modest amounts of intravenous dextrose (7.0 to 7.5 gm/hr). More rapid improvement in the acidotic state was seen in the latter group (P less than .001). The quicker decline in absolute levels and ratio of beta-hydroxybutyrate to acetoacetate when glucose was given suggests that this treatment induced mitochondrial oxidation of the reduced form of nicotinamide adenine dinucleotide (NADH). Since phosphorus is a critical cofactor necessary for NADH oxidation and the glucose-induced correction of the acidosis was associated with a rapid decline in serum phosphorus from an initial mean of 6.79 +/- .82 mg/100 ml SEM to 0.96 +/- 0.12 mg/100 ml in 24 hours, we propose that glucose enhanced the mitochondrial capacity to oxidize NADH by increasing hepatocyte phosphorus. This effect combined with decline in free fatty acid levels results in reversal of acidosis. Our data suggest that glucose provides the safest, most effective treatment for this disorder; addition of either insulin or bicarbonate is usually unnecessary.

Hidden phosphorus in popular beverages.

To maintain normal serum phosphorus levels, dialysis patient education has emphasized adherence with phosphate binder prescription and low phosphorus diet. In addition to the standard advice to avoid dairy products and legumes, education also focused on lower phosphorus protein foods and beverages. To meet the public's demands for more high quality convenience food, food-processing practices have stepped up the use of phosphorus additives. These additives are now found in beverages that were once considered low in phosphorus content.

[Fibroblast growth factor (FGF)-23 in patients with hypoparathyroidism].

Hypoparathyroidism is a well-described cause of hyperphosphatemia. We aimed to clarify the physiological role of FGF-23 in serum phosphate homeostasis in hypoparathyroidism after thyroidectomy. Increased serum FGF-23 levels were found in patients with hyperphosphatemia and hypocalcemia, caused by hypoparathyroidism after thyroidectomy. After the recovery of parathyroid function, the serum level of calcium, phosphate, and FGF-23 was normalized. Serum FGF-23 levels were significantly higher in patients with permanent hypoparathyroidism than in healthy controls. These results indicate that FGF-23 may play an important role in serum phosphate homeostasis by its up-regulation in the hyperphosphatemic condition.

Factors for increased morbidity and mortality in uremia: hyperphosphatemia.

Hyperphosphatemia is a metabolic abnormality present in the majority of patients treated by dialysis. Inorganic phosphorus (iP) can be categorized as a true uremic toxin given its known in vivo and in vitro effects and the ability to reduce these effects by normalizing iP levels. However, despite regular and adequate dialysis treatment, the goal of normalization of phosphorus levels rarely is achieved. This article briefly evaluates the significance of hyperphosphatemia in hemodialysis patients, current therapeutic approaches, and describes a new model for evaluating the dialysis prescription for iP balance.

Consequences of hyperphosphatemia in patients with end-stage renal disease (ESRD).

Hyperphosphatemia is invariably present among patients with end-stage renal disease (ESRD) and is becoming an increasingly important clinical entity. Despite concerted efforts by patients, dietitians, and nephrologists to control serum phosphorus, a recent study by Block et al found that more than 60% of patients on hemodialysis in the United States have serum phosphorus levels above the recommended goal of 5.5 mg/dL. Historically, nephrologists have been concerned about the central role of elevated serum phosphorus in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification. However, the consequences of untreated hyperphosphatemia have assumed more importance in the last few years, largely due to recent clinical studies that revealed a more sinister role of elevated serum phosphorus in increasing the mortality risk among patients with ESRD. Hemodialysis patients with serum phosphorus greater than 6.5 mg/dL were reported to have a 27% higher mortality risk than patients with serum phosphorus between 2.4 and 6.5 mg/dL. The pathophysiologic mechanisms by which persistent hyperphosphatemia enhances the mortality risk in dialysis patients are not yet completely understood. However, given that inadequate control of serum phosphorus contributes to elevated calcium-phosphorus product (Ca x P), untreated hyperphosphatemia may play a key role in cardiovascular calcification. In response to these findings, the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease have recently recommended more stringent levels for controlling serum phosphorus and Ca x P product in order to improve patients' quality of life and longevity.

Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis: results of the CARE study.

Most patients with end-stage renal disease develop hyperphosphatemia because their dietary intake exceeds phosphorus elimination by intermittent thrice-weekly dialysis. Inadequately treated hyperphosphatemia plays a central role in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification. Moreover, in the last 15 years, this biochemical abnormality has become increasingly important following the publication of two epidemiologic studies that demonstrated an association between elevated serum phosphorus and increased mortality risk in patients with end-stage renal disease. As a result, the National Kidney Foundation Kidney Disease Outcome and Quality Initiative (K/DOQI) Bone Metabolism and Chronic Kidney Disease Guidelines recommend that serum phosphorus levels be maintained between 3.5 and 5.5 mg/dL. Unfortunately, cross-sectional studies have shown a mean serum phosphorus of 6.2 mg/dL in the maintenance hemodialysis population in the United States. An alarming 60% of patients have serum phosphorus in excess of the 5.5 mg/dL level recommended by K/DOQI guidelines. In order to achieve this new target for serum phosphorus, the most efficacious and cost-effective phosphate binders currently available should be utilized. In this review, we discuss the results of the Calcium Acetate Renagel Evaluation (CARE study), which clearly demonstrated the superiority of calcium acetate over sevelamer hydrochloride for controlling serum phosphorus and calcium-phosphate product to the levels recommended by the K/DOQI guidelines.